Abstract:
In animals, both stress resistance and longevity appear to be influenced by the
insulin/insulin-like growth factor-l signaling (lIS) pathway, the basic organization of
which is highly conserved from invertebrates to vertebrates. Reduced lIS or genetic
disruption of the lIS pathway leads to the activation of forkhead box transcription factors,
which is thought to upregulate the expression of genes involved in enhancing stress
resistance, including perhaps key antioxidant enzymes as well as DNA repair enzymes.
Enhanced antioxidant and DNA repair capacities may underlie the enhanced cellular
stress resistance observed in long-lived animals, however little data is available that
directly supports this idea. I used three. experimental approaches to test the association of
intracellular antioxidant and DNA base excision repair (BER) capacities with stress
resistance and longevity: (1) a comparison of multiple vertebrate endotherm species of
varying body masses and longevities; (2) a comparison of long-lived Snell dwarf mice
and their normallittermates; and (3) a comparison of hypometabolic animals undergoing
hibernation or estivation with their active counterparts. The activities of the five major
intracellular antioxidant enzymes as well as the two rate-limiting enzymes in the BER
pathway, apurininc/apyrimidinic (AP) endonuclease and polymerase ~, were measured.
These measurements were performed in one or more of the following: (1) cultured
dermal fibroblasts; (2) brain tissue; (3) heart tissue; (4) liver tissue. My results indicate
that antioxidant enzymes are not universally upregulated in association with enhanced
stress resistance and longevity. I also did not find that BER enzyme activity was
positively correlated with longevity, in an inter-species context, though there was
evidence for enhanced BER in long-lived Snell dwarf mice. Thus, while there were instances in which enhanced antioxidant and BER enzyme activities were associated with
increased stress resistance and/or longevity, this was not universally the case, indicating
that other mechanisms must be involved. These results suggest the need to re-examine
existing 'oxidative stress' hypotheses of longevity and probe further into the molecular
physiology of longevity to discover its mechanistic basis.
